Metal-Free Direct Arylations of Indoles and Pyrroles with Diaryliodonium Salts

Ackermann, Lutz; Dell’Acqua, Monica; Fenner, Sabine; Vicente, Rubén; Sandmann, René

doi:10.1021/ol200601e

Cited by 168 publications

(105 citation statements)

References 48 publications

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“…10 A potentially more sustainable approach is the direct arylation of aromatic rings employing an aryl radical species generated in-situ. 11,12 Aryl radical species 1 can be obtained from the corresponding arylboronic acids 2, [13][14][15][16] arylhalides 3, 17 aryldiazonium salts 4 [18][19][20][21] and diaryliodonium salts 5 [22][23][24] (Figure 1). Addition of the aryl radical to a second aryl species followed by oxidation / rearomatisation then Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Retraction of “Ascorbic Acid-Promoted C–H Arylation of Heterocyclic N-Oxides through in Situ Diazotisation of Anilines: A Green and Selective Coupling Process”

Colleville¹,

Horan²,

Olazabal³

et al. 2015

Org. Process Res. Dev.

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A green and selective method for the generation of heterocyclic bi-aryl compounds through C-H arylation of heterocyclic N-oxides is presented in which ascorbic acid acts as the sole promoter for both the in-situ generation of an aryldiazonium species and the subsequent arylation. Reaction conditions were optimised through Multivariate Data Analysis and Design of Experiments methodologies resulting in further sustainability improvements, and were then applied to a range of substrates to establish the scope and limitations of the new methodology. This reaction was ultimately performed on a multigram scale and subjected to reaction calorimetry studies to support further scale-up and identify opportunities to elucidate the mechanistic course of this metal-free transformation.

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Section: Introductionmentioning

confidence: 99%

Retraction of “Ascorbic Acid-Promoted C–H Arylation of Heterocyclic N-Oxides through in Situ Diazotisation of Anilines: A Green and Selective Coupling Process”

Colleville¹,

Horan²,

Olazabal³

et al. 2015

Org. Process Res. Dev.

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“…Supporting information for this article is given via a link at the end of the document. processes are rare, they have been accomplished through the use of hypervalent iodine reagents, [19][20][21] diazonium salts, [22] or by means of electrochemistry. [23][24][25] Our group has a longstanding interest in the reaction of indoles and related heterocycles.…”

mentioning

confidence: 99%

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Chen

2017

Angewandte Chemie

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Herein, we report an unprecedented transition metal-free, coupling of indoles with aryl halides. The reaction is promoted by KOtBu and is regioselective for C3 over nitrogen. The use of degassed solvents devoid of oxygen is necessary for the success of the transformation. Preliminary studies implicate a hybrid mechanism that involves both aryne intermediates and non-propagative radical processes. Electron transfer is also a distinct possibility. These conclusions were substantiated by EPR data, isotopic labeling studies, and the use of radical scavengers and electron transfer inhibitors. Graphical AbstractMetals? What metals? Regioselective transition metal-free cross-coupling of aryl halides with indoles at C3 has been reported. The reaction proceeds through an unusual hybrid radical/aryne mechanism. Keywordsindole; transition metal-free; cross-coupling; radical; aryne Indoles with aromatic substituents at C3 are an important class of compounds, many of which possess potent biological activity. For instance, fluvastatin is an FDA-approved HMG-CoA reductase inhibitor that is used in the clinic for lowering LDL cholesterol. [1] Other C3 arylated indoles exhibit pico-to nanomolar inhibitory actions against a wide range of biological targets and processes such as the progesterone receptor, [2] COX-II enzyme, [3] carbonic anhydrase I and II, [4] and tubulin polymerization, [5] etc.The direct introduction of aromatic groups onto an extant indole nucleus at C3 is typically carried out by transition metal-catalyzed cross-coupling reactions (Figure 1). [2,[6][7][8][9][10][11][12][13][14] Methods utilizing C-H activation have also been reported. [15][16][17][18] While transition metal-free Correspondence to: Jimmy Wu. Supporting information for this article is given via a link at the end of the document. processes are rare, they have been accomplished through the use of hypervalent iodine reagents, [19][20][21] diazonium salts, [22] or by means of electrochemistry. [23][24][25] Our group has a longstanding interest in the reaction of indoles and related heterocycles. [26][27][28][29] Herein, we disclose a new approach for the intermolecular C3 arylation of unprotected indoles with simple aryl halides. The reaction is promoted by KOtBu and does not require the use of transition metal catalysts. Preliminary mechanistic investigations point towards an unusual hybrid reaction pathway that exhibits features of both radical and aryne intermediates. Although Daugulis and Tu have reported a limited number of basepromoted C2-and N-selective arylation reactions of indoles, [30][31][32] there appear to be very few precedents for C3-selective variants [32,33] and none that proceed by the proposed hybrid radical/aryne mechanism. HHS Public AccessOptimization studies were carried out on the reaction between indole (1a) and iodobenzene (Table 1). A brief solvent survey identified DMF and DMSO as the only effective solvents (entries 1-5). A reaction performed in the dark resulted in similar yield and selectivity (entry 7 vs 5). ...

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“…In 2011, C-H arylations of indoles and pyrroles with aryliodonium salts as coupling partner were reported by Sanford [65] and Ackermann [66]. As mentioned earlier, previous studies from the Sanford group [52] had shown that palladium catalysts can assist the direct arylation of indoles using aryliodonium salts; more recent studies attempted the coupling of aryliodonium salts with more sterically hindered heteroarenes such as 2,5-disubstituted pyrroles.…”

Section: Indoles and Pyrroles -Electron-rich Heteroarenesmentioning

confidence: 98%